In the past year, we have focussed on mechanisms that determine the interaction of staphylococci with innate host defense, specifically how S. epidermidis and S. aureus sense and respond to antibacterial peptides. [unreadable] [unreadable] To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides represent a key component of innate host defense, especially in phagocytes and on epithelial surfaces. However, it is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms of Gram-positive bacteria and is unrelated to the Gram-negative PhoP/PhoQ system. It contains a classical two-component signal transducer and an unusual third protein, all of which are indispensable for signal transduction and antimicrobial peptide resistance. Our study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development. Moreover, we demonstrated that many antimicrobial peptides (including negatively charged peptides that do not activate the beforementioned sensory system) induced differential expression of global regulatory systems, leading to increased expression of proteases with the capacity to degrade antimicrobial peptides, particularly S. epidermidis SepA. A similar induction of extracellular proteolytic activity was found in S. aureus, suggesting a common regulatory mechanism in staphylococci. Notably, inactivation of dermcidin by SepA was much more effective than of the tested cationic peptides. The ability to react to the unusual, anionic dermcidin with effective countermeasures likely contributes to the extraordinary success of staphylococci as colonizers and infective agents on human epithelia. Our study indicates that staphylococci can react to human antimicrobial peptides by specific mechanisms of resistance and establishes a crucial role for staphylococcal proteases in the interaction with human innate host defense.